Familial SYNGAP1 variants define the boundaries of a complex neurodevelopmental disorder with epilepsy.

Objective: SYNGAP1-related disorders are common neurodevelopmental conditions characterized by autism spectrum disorder, developmental delay, intellectual disability, and a range of generalized seizure types. Disease-causing variants in SYNGAP1 typically occur de novo. This study aims to characterize inherited cases of SYNGAP1-related disorders.

Methods: Here we report three families including eight total individuals with inherited, protein-truncating variants in SYNGAP1, recruited through a natural history study. In two of the families, the proband inherited their pathogenic variant from a heterozygous parent. In the remaining family, the variant was inherited from a mosaic parent. This study additionally reports two families with inherited missense variants classified as variants of uncertain significance, which are not clearly diagnostic at this time.

Results: Phenotypes in affected children and parents included both typical and attenuated SYNGAP1 presentations, including a single individual with a mosaic SYNGAP1 variant who was clinically unaffected. Among the individuals with protein-truncating variants, generalized epilepsy was observed in six individuals, autism spectrum disorder in two individuals, and developmental delay or intellectual disability in all individuals with germline variants.

Significance: We demonstrate that SYNGAP1-related disorder can occur in families and that clinical presentations of familial cases are not limited to milder phenotypes. We estimate that 3% of cases of SYNGAP1-related disorder are inherited. Recognition of familial SYNGAP1-related disorders delineates edge cases of a relatively common neurodevelopmental disorder and has implications for variant interpretation and clinical practice.